In the late 1960s, Reiner acted in bit roles in several television shows including Batman, The Andy Griffith Show, Room 222,Gomer Pyle, U.S.M.C. and The Beverly Hillbillies. He began his career writing for the Smothers Brothers Comedy Hour in 1968 and 1969. Two years later, Reiner became famous playing Michael Stivic, Archie Bunker's liberal son-in-law, on Norman Lear's 1970s situation comedy All in the Family, which was the most-watched television program in the United States for five seasons (1971–1976). The character's nickname became closely associated with him, even after he had left the role and went on to build a high-profile career as a director. Reiner has stated, "I could win the Nobel Prize and they'd write 'Meathead wins the Nobel Prize'."[3] For his performance, Reiner won two Emmy Awards in addition to three other nominations and five Golden Globe nominations. After an extended absence, Reiner has recently returned to television acting with a recurring role on New Girl (2012–present).

In 1972, Reiner, Phil Mishkin, and Gerry Isenberg created the situation comedy The Super for ABC. Starring Richard S. Castellano, the show depicted the life of the harried Italian American superintendent of a New York City apartment building and ran for 10 episodes in the summer of 1972. Reiner and Mishkin co-wrote the premiere episode.

Beginning in the 1980s, Reiner became known as a director of several successful Hollywood films that spanned many different genres. Several of these film remains highly popular with fans and critics. Some of his earlier films include cult classics such as the rock-band mockumentaryThis Is Spinal Tap (1984) and the comedic fantasy film The Princess Bride (1987), as well as his period piece coming of age tale Stand by Me (1986), which was also highly acclaimed. He often collaborates with film editor Robert Leighton, whom he also shares with fellow director-actor Christopher Guest as their go-to editor.

Reiner has devoted considerable time and energy to liberal activism in recent years. His lobbying as an anti-smoking advocate in particular, earned his likeness a satirical role in a South Park episode titled "Butt Out".

In 1998, Reiner chaired the campaign to pass Prop 10, the California Children and Families Initiative, which created First 5 California, a program of early childhood development services, funded by a tax on tobacco products. He served as the first chairman of First 5 California, from 1999 to 2006. Reiner came under criticism for campaigning for a ballot measure (Prop 82) to fund state-run preschools while still chair of the First Five Commission, causing him to resign from his position on March 29, 2006. An audit was conducted, and it concluded that the state commission did not violate state law and that it had clear legal authority to conduct its public advertising campaigns related to preschool. In the end, Prop 82 failed to win approval, garnering only 39.1% support.

Reiner is a member of the Social Responsibility Task Force, an organization advocating moderation where social issues (such as violence and tobacco use) and the entertainment industry meet. He is also active in environmental issues, and he successfully led the effort to establish California's Ahmanson Ranch as a state park and wildlife refuge rather than as a commercial real estate development. He introduced Spinal Tap at the London Live Earth concert in July 2007.

Reiner was mentioned as a possible candidate to run against California Governor Arnold Schwarzenegger in 2006 but decided not to run for personal reasons. He campaigned extensively for Democratic presidential nominee Al Gore in the 2000 Presidential election, and he campaigned in Iowa for Democratic Presidential candidate Howard Dean just before the 2004 Iowa caucuses. He endorsed Hillary Clinton for president for the 2008 election. In 2015, he donated US$10,000 to Correct the Record, a political action committee which supports Hillary Clinton's 2016 presidential campaign.[7] Since the 2016 election, he has continued to campaign against Donald Trump, calling him a racist, sexist, anti-gay, and anti-Semitic, and compared him to the Nazi police at Auschwitz.[8]

Rob Reiner married actress/director Penny Marshall in 1971. Marshall's daughter, actress Tracy Reiner (A League of Their Own), was from a previous marriage to Michael Henry. Reiner and Marshall divorced in 1981.[9]

Reiner was introduced to his future wife, photographer Michele Singer, while directing When Harry Met Sally. The meeting not only resulted in his deciding to change the ending of that movie,[10] but he also married Singer in 1989. They have three children. In 1997, Reiner and Singer founded the "I Am Your Child Foundation," and in 2004, they founded the "Parents' Action for Children," a non-profit organization with a dual purpose: a) to raise awareness of the importance of a child's early years by producing and distributing celebrity-hosted educational videos for parents, and b) to advance public policy through parental education and advocacy.[11]

Reiner has stated that his childhood home was not observantly Jewish, although he did have a Bar Mitzvah ceremony.[12] He identified himself as having no religious affiliation on the January 13, 2012, episode of Real Time with Bill Maher.[13] Reiner later told Huffington Post contributor Debra Oliver that while he rejected organized religion, he was sympathetic to the ideas of Buddhism.[13]

In addition to his four children, Reiner has five grandchildren, through his step-daughter Tracy.[14]